It is known that chloride ions (Cl−) not only manage transportation of water/electrolyte, secretion and regulation of cell volume but also play an important role as a factor affecting the response of cells.
For example, the transition of chloride ions into or out of cells concurrently accompanies the transport of water and electrolyte, which results in the regulation of cell volume. Therefore, it is suggested that chloride ions play an important role in the growth and division of cells and the programmed cell death that accompany an abrupt change in the cell volume.
In the brain, it is known that inhibitory regulation works in the central nervous system by maintaining chloride ions in the nerve cells at a low level. It is also known that chloride ions play an important role in inhibiting anxiety and spasm, and regulating sleep, memory and circadian rhythm.
In the bowel, it is known that chloride ions are deeply involved with such pathology as diarrhea and constipation, and when opioid such as morphine is administered to bring abnormal secretions of electrolyte such as chloride ions and fluid, it will cause intractable constipation. Other diseases known to be caused by an abnormality in the balance of chloride ions include myotonia atrophica, diseases showing hypercalciuria such as calculus renum, anxiety, insomnia, cystic fibrosis, epilepsia, anesthesia, asthma, bronchitis and neuropathy.
A chloride channel is an ion-transport membrane protein for transporting chloride ions. It has been reported that various kinds of chloride channels are present in the cell membrane of nerve, muscle and epithelium, and they are involved with various physiological functions and cytophylaxis mechanisms.
For example, a chloride channel named CFTR (cystic fibrosis transmembrane conductance regulator) was discovered in trying to find the cause of cystic fibrosis. Cystic fibrosis is an autosomal recessive inheritary disease best known in the Caucasian race. The variation of genes, which is the cause of this disease, occurs in CFTR genes due to the reduced permeability of chloride ions caused by the deficiency in functions of CFTR in the epithelial cells of air duct, pancreas, bowel, perspiratory gland, alimentary tract, etc.
Further, a chloride channel cloned by cramp fish's electric organ and named ClC-0 was later found to form a large family (ClC family). Examples of ClC family are: ClC-1 present in the skeletal muscle of mammals; ClC-2 present in the epithelium of various organs; ClC-3 and ClC-4 distributed in hippocampus, cerebellum, etc.; ClC-5 present in lung, kidney, etc.; ClC-6 and ClC-7 present in brain, testis, skeletal muscle, kidney, etc.; and ClCK-1 and ClCK-2 specifically shown only in kidney. It is known that the abnormality in ClC-1 causes congenital myotonia and the abnormality in ClC-5 causes hereditary nephrolithiasis.
Accordingly, a compound which can open chloride channels and promotes chloride ion transportation are considered to affect on various cell functions and cytophylaxis mechanisms, and also considered to be useful for the treatment of pathology occurring because of abnormal chloride ion balance within or outside the cells due to the reduced permeability of chloride ions by some cause.
Prostaglandins (hereinafter, referred to as PG(s)) are members of class of organic carboxylic acids, which are contained in tissues or organs of human or other mammals, and exhibit a wide range of physiological activity. PGs found in nature (primary PGs) generally have a prostanoic acid skeleton as shown in the formula (A):

On the other hand, some of synthetic analogues of primary PGs have modified skeletons. The primary PGs are classified to PGAs, PGBs, PGCs, PGDs, PGEs, PGFs, PGGs, PGHs, PGIs and PGJs according to the structure of the five-membered ring moiety, and further classified into the following three types by the number and position of the unsaturated bond at the carbon chain moiety:                Subscript 1: 13,14-unsaturated-15—OH        Subscript 2: 5,6- and 13,14-diunsaturated-15—OH        Subscript 3: 5,6-, 13,14-, and 17,18-triunsaturated-15—OH.        
Further, the PGFs are classified, according to the configuration of the hydroxyl group at the 9-position, into α type (the hydroxyl group is of an α-configuration) and β type (the hydroxyl group is of a β-configuration).
PGE1, PGE2 and PGE3 are known to have vasodilation, hypotension, gastric secretion decreasing, intestinal tract movement enhancement, uterine contraction, diuretic, bronchodilation and anti ulcer activities. PGF1α, PGF2α, and PGF3α have been known to have hypertension, vasoconstriction, intestinal tract movement enhancement, uterine contraction, lutein body atrophy and bronchoconstriction activities.
It has been reported that PGE1 and PGF2α stimulate secretion of chloride ions in rabbit ileum (Nature vol. 238, 26-27, 1972, the cited reference is herein incorporated by reference) and PGE2 induces secretion of chloride ions in human jejunum (Gastroenterology vol. 78, 32-42, 1980, the cited reference is herein incorporated by reference). It has been also reported that PGE2 regulates chloride ion transportation in the endometrial epithelial cells (Journal of Physiology vol. 508, 31-47, 1998, the cited reference is herein incorporated by reference). Meanwhile, it has been reported that platelet chloride transportation did not respond to PGE1 in cystic fibrosis patients (European Journal of Clinical Chemistry and Clinical Biochemistry vol. 33, No. 6, 329-335, 1995, the cited reference is herein incorporated by reference) and a prostaglandin analogue (misoprostol) did not promote chloride secretion in cystic fibrosis patients (American Journal of Human Genetics Vol. 67, No. 6, 1422-1427, 2000, the cited reference is herein incorporated by reference).
Further, it has been reported that PGE2 opens a housekeeping basolateral chloride channel of rabbit (Journal of Biological Chemistry, 270(32) 1995, the cited reference is herein incorporated by reference). Furthermore, it has been reported that PGE2 and PGF2 α activate chloride conductance in mouse endometrial epithelial cells via CFTR (Biology of Reproduction, 60(2) 1999).
However, it is not known how prostaglandin compounds act on chloride channels, especially on ClC channels.